The goal of this proposal is to conduct preclinical and animal-model research towards the development of practical immunogens that may constitute, or contribute to, an effective prophylactic vaccine against HIV-1 infection. We will execute projects aimed at: 1) determining the correlates of protective immunity elicited in rhesus macaques by a live, attenuated strain of SIV; 2) characterizing a panel of HIV-1's to select an ideal viral strain for use to construct candidate vaccines, to develop an appropriate SHIV-macaque model, and to modify the envelope glycoprotein for enhanced immunogenicity; 3) designing and evaluating vaccine strategies based on priming with either recombinant vaccinia or DNA vaccines, followed by boosting with pseudovirions or different forms of the envelope glycoproteins. Of note is that we will focus on the development and evaluation of immunogens based on HIV-1 clade C, the most prevalent subtype worldwide. We plan to conduct research by an iterative process, in which we will continually refine laboratory-based research programs based upon the results of our animal experiments. We emphasize that we are proposing not a basic science program, but one specifically aimed at the development and testing of vaccine candidates. Although no clinical evaluation is proposed here, we are prepared to expand our horizons should results of preclinical and animal studies warrant this. We hope that has promising vaccine strategies emerge from our proposed studies, they can be assessed in human populations, especially in regions where subtype C is spreading rapidly, notably in southern Africa, India and southwestern China.